Expert perspectives on ECCO2R for acute hypoxemic respiratory failure: consensus of a 2022 European roundtable meeting

Background By controlling hypercapnia, respiratory acidosis, and associated consequences, extracorporeal CO2 removal (ECCO2R) has the potential to facilitate ultra-protective lung ventilation (UPLV) strategies and to decrease injury from mechanical ventilation. We convened a meeting of European intensivists and nephrologists and used a modified Delphi process to provide updated insights into the role of ECCO2R in acute respiratory distress syndrome (ARDS) and to identify recommendations for a future randomized controlled trial. Results The group agreed that lung protective ventilation and UPLV should have distinct definitions, with UPLV primarily defined by a tidal volume (VT) of 4–6 mL/kg predicted body weight with a driving pressure (ΔP) ≤ 14–15 cmH2O. Fourteen (93%) participants agreed that ECCO2R would be needed in the majority of patients to implement UPLV. Furthermore, 10 participants (majority, 63%) would select patients with PaO2:FiO2 > 100 mmHg (> 13.3 kPa) and 14 (consensus, 88%) would select patients with a ventilatory ratio of > 2.5–3. A minimum CO2 removal rate of 80 mL/min delivered by continuous renal support machines was suggested (11/14 participants, 79%) for this objective, using a short, double-lumen catheter inserted into the right internal jugular vein as the preferred vascular access. Of the participants, 14/15 (93%, consensus) stated that a new randomized trial of ECCO2R is needed in patients with ARDS. A ΔP of ≥ 14–15 cmH2O was suggested by 12/14 participants (86%) as the primary inclusion criterion. Conclusions ECCO2R may facilitate UPLV with lower volume and pressures provided by the ventilator, while controlling respiratory acidosis. Since recent European Society of Intensive Care Medicine guidelines on ARDS recommended against the use of ECCO2R for the treatment of ARDS outside of randomized controlled trials, new trials of ECCO2R are urgently needed, with a ΔP of ≥ 14–15 cmH2O suggested as the primary inclusion criterion. Supplementary Information The online version contains supplementary material available at 10.1186/s13613-024-01353-8.


Background
Clinical data suggest that mechanical ventilation (MV) can contribute to the negative outcomes in patients with acute respiratory distress syndrome (ARDS) through ventilator-induced lung injury (VILI) [1][2][3].The ARDSNet investigators demonstrated that limiting tidal volume (V T ) to 6 mL/kg of predicted body weight (PBW) and plateau pressure (P Plat ) to < 30 cm H 2 O improved survival.However, this approach may not be fully protective as ~ 30% of patients exhibit tidal hyperinflation along with an increase in proinflammatory mediators in bronchoalveolar lavage fluid, a typical signal for VILI [4,5].Reducing V T even further to 4 mL/kg and P Plat to < 25 cmH 2 O, a strategy termed "ultra-protective ventilation", has been proposed to reduce VILI effects [6][7][8].Furthermore, other variables of risk reduction for VILI have been discussed: Amato et al. [9] suggested reduction of driving pressure (ΔP), reduction of respiratory rate [10,11] and/or mechanical power [12][13][14][15] are other variables to be discussed in this context.However, this strategy entails the risks associated with hypercapnia and severe respiratory acidosis [16][17][18].
As an adjunct to MV, extracorporeal CO 2 removal (ECCO 2 R) aims to clear CO 2 , enabling ultra-protective lung ventilation while limiting hypercapnia and respiratory acidosis [19][20][21][22].In 2019, a European ECCO 2 R user group meeting identified factors influencing patient selection and clinical decision-making, as well as how to implement ECCO 2 R in the intensive care unit (ICU) [17].The group considered ARDS to be the primary indication for ECCO 2 R, with the treatment goal being to facilitate ultra-protective lung ventilation by decreasing V T , P Plat , ΔP, and RR [17].
Since this framework was proposed, experience of ECCO 2 R and ultra-protective lung ventilation has increased.The COVID-19 pandemic provided experience of delivering ECCO 2 R to different patient groups [23][24][25].While the REST study (NCT02654327) reported no difference in 90-day mortality in patients receiving ultra-low V T ventilation (ULTV) with ECCO 2 R compared with those receiving low V T ventilation (LTV) without ECCO 2 R [26], a secondary analysis suggested that the use of ECCO 2 R may improve survival in patients with a ventilatory ratio (VR, ≥ 3; a simple bedside index of impaired efficiency of ventilation, which correlates well with physiological dead space fraction) [27,28].However, uncertainty remains around the use of ECCO 2 R in ARDS, and the recent European Society of Intensive Care Medicine (ESICM) guidelines recommended that the use of ECCO 2 R for the treatment of ARDS should be limited to randomized controlled trials [29].We therefore convened the second European ECCO 2 R Expert Roundtable Meeting to update the framework for ECCO 2 R and to outline further research in this area.

Participants
The ECCO 2 R Expert Roundtable Meeting was held in Brussels on the 5 October 2022 and was attended by 16 clinicians (1 chair [AC] plus 15 respondents) who regularly provide ECCO 2 R in clinical centers across Europe.Each participant was a senior clinician or an intensivist with direct clinical experience of ECCO 2 R, with several of the participants being principal investigators in recently completed or ongoing clinical trials.JK and KH are employees of Baxter who were engaged in the development of the questionnaire.They did not participate in the roundtable discussion but, like all other authors, they participated in drafting the manuscript and critically revising it for important intellectual content.There was no modification of the intellectual content by Baxter employees other than the listed authors.All authors take responsibility for the final content of the manuscript.Conflict of interest declarations for the attendees can be found at the end of the manuscript.

Objectives
The objectives of the Expert Roundtable Meeting were to understand current clinical practice for ECCO 2 R in patients with acute hypoxemic respiratory failure, including the clinical rationale for the use of ECCO 2 R, the criteria used for initiation, maintenance, and discontinuation in patients with mild-to-moderate ARDS, and practical considerations, including anticoagulation and vascular access strategies.The meeting also aimed to assess the impact of recent publications investigating the use of ECCO 2 R to support ultra-protective lung ventilation for acute respiratory failure [26], as well as the impact of the COVID-19 pandemic on current and future standards of practice.

Data collection and analysis
A modified Delphi-based methodology was used to assess the clinicians' views on ECCO 2 R over four rounds of iterative questioning, including an anonymous premeeting survey, a live survey during the meeting, and two anonymous post-meeting surveys (Table 1).The meeting questions, as well as the pre-meeting and post-meeting surveys, were developed by AC in collaboration with JK, with independent medical writing support funded by Baxter.The questions are available in the supplementary appendix.JK and KH did not participate in answering the surveys.
The Round 1 pre-meeting survey consisted of a PDF questionnaire that was circulated to each participant individually in advance of the meeting, with results analyzed anonymously.Results from the Round 1 survey were presented to the group and used to inform the questions asked in the Round 2 meeting, which was moderated by an independent facilitator.In Round 2, participants were divided into four subgroups and questions were presented to the group by an independent facilitator.For closed questions, participants provided their responses anonymously through a web-based voting system.For open questions, responses from each group were collected after a period of discussion to facilitate interaction between participants.JK and KH were present as Baxter employees during the meeting but were not permitted to provide answers or responses.To further explore questions and topics raised during the meeting, a first post-meeting survey (Round 3) was shared with the authors.Based on the Round 3 survey and literature published following the meeting, including the secondary analysis of the REST trial, the ESICM guidelines and the VT4COVID trial [28][29][30], a second post-meeting survey (Round 4) was shared with the authors to understand their definition of ultra-protective ventilation and the role of ECCO 2 R.Both Round 3 and 4 surveys consisted of PDF questionnaires that were shared with each participant individually and the results were analyzed anonymously.
Responses to the survey questions at each round were evaluated to determine the level of agreement between participants.A threshold of ≥ 80% of participants in agreement was defined as a "consensus." A threshold of ≥ 50% of participants in agreement was defined as a "majority, " while < 50% was defined as "no agreement." These thresholds are consistent with the analysis conducted in 2019 [17].
To facilitate the analysis of responses for questions regarding respiratory parameters used for the implementation of lung protective ventilation and ECCO 2 R, a ranked scoring system was employed.Participants were asked to score respiratory parameters in order of perceived importance, giving them a score (e.g. from 1 to 5, depending on the number of variables).Scores were then combined to give a total score for each parameter, with higher scores indicating a higher perceived importance.

Participant experience
The participants at the meeting were experienced clinicians who regularly provide ECCO 2 R in clinical centers across Europe; the average number of patients treated with ECCO 2 R therapy in their ICU/unit per year was 8 (range 1-18).Regarding patients with mild-to-moderate ARDS (defined by the 2012 Berlin definition), the average number of admissions per year to their ICU/unit was 112 (range 40-250).Participants used all available devices for ECCO 2 R present in the EU at that time, including devices from ALung, B-Braun and Fresenius.The majority of

Table 1 Overview of the modified Delphi method
Each step was a distinct process that was completed before the following step was initiated.Results and discussions from each step were independently analyzed and informed the direction and content of the subsequent step, e.g. if the group were split on a topic, then clarifying questions were crafted to guide the discussions in the following step(s) to identify and explore points of consensus or difference ECCO 2 R extracorporeal carbon dioxide removal, GPP Good Publication Practice, ICU intensive care unit, PDF portable document format

Objective(s)
Steps Format

Definitions of lung protective ventilation and ultra-protective lung ventilation
The majority of participants (57%) agreed that lung protective ventilation and ultra-protective lung ventilation should have distinct definitions, with lower targets for V T , ΔP, P Plat , and RR identified as the parameters that define ultra-protective lung ventilation vs. more conventional lung protective ventilation.Participants ranked V T , ΔP, P Plat , and RR as the four most important respiratory parameters to monitor when implementing a protective ventilation strategy.In subsequent rounds, participants agreed that a protective ventilation strategy for patients with mild-to-moderate ARDS should have a target V T of 6 mL/kg PBW, maximum ΔP of 15 cmH 2 O, and maximum P Plat of 29-30 cmH 2 O (majority, Fig. 1A-C).No agreement was reached on maximum RR, with 10 participants selecting values of 21-30 breaths per minute (BPM) (Fig. 1D).Based on the ECCO 2 R data published after the meeting, the majority of participants (63%) indicated that ultra-protective lung ventilation should have a maximum V T ≤ 6 mL/kg PBW, with 6, 2, 7, and 1 participants defining V T as ≤ 6, ≤ 5, ≤ 4, and ≤ 3 mL/kg PBW, respectively (Fig. 2A).The majority of participants consider a VT < 4 mL/kg as the definition for ULTV.

Use of ECCO 2 R to facilitate protective ventilation in patients with ARDS
All participants indicated that ultra-protective lung ventilation facilitated by ECCO 2 R would require a maximum ΔP (100%, consensus), with the majority (56%) selecting 14-15 cmH 2 O as their preference; 12-13 cmH 2 O and 16-17 cmH 2 O were selected by three participants each (19%, Fig. 2B).Furthermore, 10 participants (majority, 63%) would select patients using a minimum PaO 2 :FiO 2 of > 100 mmHg (> 13.3 kPa) and 14 (consensus, 88%) would select a minimum VR of > 2.5-3.Fourteen (93%) participants agreed that ECCO 2 R would be needed in the majority of patients to implement ultra-protective lung ventilation (consensus) (Fig. 2C).When discontinuing ECCO 2 R, pH, ΔP, RR, and P plat were indicated as being the four most important respiratory parameters to consider (evaluated with sweep gas off on the ECCO 2 R device).In subsequent rounds, most participants would discontinue ECCO 2 R once pH reached > 7.3 (majority) (Table 2).No agreement was reached on thresholds for ΔP, RR, or P plat .

Anticoagulation strategy for ECCO 2 R
Fourteen out of 15 participants (93%) would use unfractionated heparin for anticoagulation when implementing ECCO 2 R (consensus), with one participant stating they would use regional citrate-based anticoagulation (although this treatment is not recommended with flow higher than 150 mL/min) (Table 3).Among participants who preferred heparin, the majority agreed they would target an activated partial thromboplastin time ratio of 1.5-2.0× control (majority).Half of participants (7/14) reported using anti-Xa testing, with all of them agreeing on a target range of 0.3-0.5 IU/mL (consensus).No agreement was reached on bolus or infusion dosage for unfractionated heparin.

Optimal blood flow rate for ECCO 2 R and vascular access
Most participants selected either a range of 251-350 mL/ min or 351-450 mL/min as the minimum blood flow rate they believed was required for effective use of ECCO 2 R (Fig. 3A).A majority of participants (73%) believed that a minimum CO 2 removal rate of 80 mL/min delivered by technology based on peristaltic (roller) pumps as in renal support devices was required for ECCO 2 R to be effective (Fig. 3B).The right internal jugular vein was the preferred vascular access point for the majority of participants (Table 4); however, femoral access was discussed as suitable, especially in conscious patients.All participants preferred using a double-lumen catheter (consensus), with most participants specifying a length of 16-17 cm (for the right internal jugular access) and a diameter of 14 French (both majority).All considered the use of vascular ultrasound necessary to safely guide venous catheter insertion using the Seldinger technique (consensus) (Table 5).

Discussion
This consensus provides fresh insights into the use of ECCO 2 R for mitigating VILI in patients with ARDS.The group agreed that lung protective ventilation and ultra-protective lung ventilation should have distinct   [29].To this end, the group provided recommendations to guide the development of a trial to help overcome the uncertainties around the use of ECCO 2 R. The previous ECCO 2 R Roundtable Meeting was held in July 2019.Since then, further insights into lung protective and ultra-protective lung ventilation and the use of ECCO 2 R have emerged.Firstly, the REST trial, the first large-scale randomized controlled trial of patients receiving MV facilitated by ECCO 2 R, was halted due to futility [26].No significant benefit of ECCO 2 R on 90-day mortality vs. standard care was observed (41.5% vs. 39.5%, respectively; p = 0.68) [26].In addition, serious adverse events were reported more commonly in the ECCO 2 R group, the majority related to bleeding complications, including intracranial hemorrhage.Bleeding complications associated with ECCO 2 R were indeed identified by our panel as one of the major endpoints to evaluate in a future trial of ECCO 2 R in ARDS.They also suggested unfractionated heparin should remain the firstline anticoagulant for ECCO 2 R, although new drugs with more favorable efficacy/safety profiles are currently under development and evaluation [31].The REST trial had other major limitations.At randomization, ARDS was present in only 59% of the patients, ΔP was < 15 cm H 2 O in 50% of patients and, despite marked hypoxemia (median PaO 2 :FiO 2 , 118 mmHg), the median positive end-expiratory pressure (10 cm H 2 O) was lower than in other ARDS trials with similar patients and only 11% of the patients had been proned.On Day 2 post-randomization, the decreases in V T (6.3-4.5 mL/kg) and in ΔP (15-12 cm H 2 O) from baseline were modest, while increases in the RR (from 24 to 27 BPM) and in PaCO 2 (from 54 to 61 mmHg) were observed.These data suggest that the device used in this study may have provided insufficient CO 2 removal to reach ultra-protective ventilation while controlling respiratory acidosis.Furthermore, as noted by the trial authors, most of the trial's study sites were naive to the intervention, and inexperience may have negatively affected outcomes [26].Interestingly, a secondary analysis of the REST trial has suggested a benefit of low V T ventilation facilitated by ECCO 2 R on 90-day survival in a subset of the patients who had a high VR (> 3) and in patients with PaO 2 :FiO 2 110 mmHg or higher [28].
Secondly, the VT4COVID study conducted across 10 ICUs in France compared LTV (6 mL/kg PBW) or ULTV (4 mL/kg PBW) during the COVID-19 pandemic.There was no significant difference in the primary composite outcome of all-cause mortality at Day 90 and ventilatorfree days at Day 60.Forty-six (44%) of 105 patients in the ULTV group and 43 (39%) of 109 in the LTV group died by Day 90 (absolute difference 4% [− 9 to 18]; p = 0.52) [30].Severe respiratory acidosis in the first 28 days was higher in the ULTV group than in the LTV group (33% vs. 13%; absolute difference 20% [95% confidence interval 9-31]; p = 0.0004), suggesting the potential need for ECCO 2 R to facilitate ultra-protective lung ventilation.A major limitation of this trial is that the median ΔP was only 11 cm H 2 O at inclusion (with a modest reduction in ΔP of only 2 mm H 2 O in the ULTV group), with the benefit of further lowering V T being very unlikely   a Two participants declined to answer this question; level of agreement has been calculated using the total number of respondents A threshold of ≥ 80% of participants in agreement was defined as "consensus." A threshold of ≥ 50% of participants in agreement was defined as a "majority, " while < 50% was defined as "no agreement" to outweigh the possible risks of heavy sedation, neuromuscular blockade, and diaphragm deconditioning.In a further development, the authors of the VT4COVID trial have since indicated that they are analyzing their trial database to identify a threshold of ΔP above which ULTV would be beneficial [30].Another limitation of the VT4COVID trial is that the possible benefit of the reduction in TV in the ULTV group may have been masked by the increase of respiratory rates, with such increases in respiratory rates potentially a consequence of respiratory acidosis and hypercapnia in this population.Although not necessarily supporting the concept of ULTV, these observations may suggest that its application without sufficient extracorporeal reduction of CO 2 load may limit its beneficial effects for patients.

Parameter
Thirdly, the ESICM guidelines on ARDS recommended against the use of ECCO 2 R for the treatment of ARDS outside of randomized controlled trials [29].This is based on a meta-analysis of the primary analysis of the REST trial and the smaller Xtravent trial, which suggests the use of ECCO 2 R did not reduce mortality as well as the side effects experienced in the REST trial in patients receiving ECCO 2 R.However, the ESICM experts do acknowledge the need for further research to clarify the current uncertainty around ECCO 2 R; specifically, understanding device-specific safety and efficacy profiles, the identification of long-term multidimensional outcomes, and defining a population of patients with ARDS who may respond to ECCO 2 R [29].Indeed, during our meeting, there was a recurring discussion on the importance of a patient-centric approach to ECCO 2 R, highlighting that the parameters necessary for initiation and discontinuation of protective ventilation and/or ECCO 2 R must be adapted to the patient's disease severity, comorbidities, and ventilatory parameters associated with lung injury.Specifically, the participants emphasized that parameters reflecting alterations in lung mechanics, such as an increase in ΔP, might serve as better inclusion criteria for ECCO 2 R in patients with acute hypoxemic respiratory failure than the degree of hypoxemia.The group also Table 5 Preliminary suggestions for the design of a future randomized trial of ECCO 2 R for patients with acute hypoxemic respiratory failure believed that a minimum CO 2 removal rate of 80 mL/ min delivered by continuous renal support machines was required for ECCO 2 R to be effective, with a short, double-lumen catheter inserted into the right internal jugular vein as the preferred vascular access.Furthermore, we note the type of device use to deliver ECCO 2 R may have some import.That is, at the flow rates typically used for ECCO 2 R (~ 300 to ~ 1500 mL/min), centrifugal devices (used in the REST trial) [26] have an associated risk of hemolysis and destruction of platelets [32] that may not occur with peristaltic pumps.Our recommendations provided here on the use of ECCO 2 R and on clinical trial design should aid the development of a trial that could help answer the questions posed by the ESICM guidelines on ARDS.
This work does have some limitations.Firstly, the findings relate to the experiences of a relatively small number of physicians from centers across Europe and do not replace the need for a randomized controlled trial to determine the optimal use of ECCO 2 R to facilitate LTV strategies.Secondly, the group focused on the use of ECCO 2 R to facilitate ventilation in patients with ARDSthese experiences may not translate to other rarer indications.Thirdly, we did not include discussions related to the amount of CO 2 removal required depending on ideal/ predicted body weight or other external factors that could influence a patient's CO 2 production.The amount of CO 2 that is produced by the patient is dependent on multiple factors (such as muscle activity, inflammatory reactions and nutrition).As a result, it cannot be defined easily and there is no method available that can be used easily at the bedside to determine this production rate reliably.This is another reason why more physiological and interventional studies are needed to explore the ability of the ECCO 2 R device to control hypercapnia while providing ultra-protective lung ventilation.Although the authors took every opportunity to ensure all relevant major articles were cited when constructing surveys, a comprehensive systematic literature analysis was considered out of scope of this project.Readers are reminded that the discussions outlined here are the authors' personal experiences and are not a replacement for formal guidelines.Practicing clinicians should continue to prioritize their patients' individual needs and consult guidelines.

Conclusions
The authors consider that ECCO 2 R may facilitate UPLV with lower volume and pressures by the ventilator while controlling respiratory acidosis.ECCO 2 R may be delivered using blood flows currently delivered by continuous renal support machines, providing that a minimum CO 2 removal rate of 80 mL/min can be obtained.Since recent ESICM guidelines on ARDS recommended against the use of ECCO 2 R for the treatment of ARDS outside of randomized controlled trials, a new trial of ECCO 2 R is now urgently needed (with ΔP of ≥ 14-15 cmH 2 O suggested as the primary inclusion criterion).

6 D 11 - 30 Fig. 1
Fig. 1 Acceptable threshold values for respiratory parameters when implementing protective ventilation to minimize or avoid VILI for a patient with mild-to-moderate ARDS.14/15 participants answered this question.≥ 12 responses indicate consensus, ≥ 7 responses indicate a majority, and < 7 responses indicate no agreement

"Fig. 2
Fig. 2 Ventilatory objectives for ultra-protective lung ventilation.Target V T (A) and driving pressure (B) thresholds for ultra-protective lung ventilation as defined by the participants.(C) Rate of participants stating that ECCO 2 R would be required to implement ultra-protective lung ventilation.All participants answered this question.≥ 12 responses indicate a consensus, ≥ 8 responses indicate a majority, and ≤ 7 responses indicate no agreement Fig. 3 Minimum requirements for ECCO 2 R therapy.A Minimum blood flow rate required for effective use of ECCO 2 R. All 15 participants answered this question.≥ 12 responses indicate consensus, ≥ 8 responses indicate a majority, and ≤ 7 responses indicate no agreement.B Minimum CO 2 removal rate for an ECCO 2 R device.14/15 participants answered this question.≥ 12 responses indicate consensus, ≥ 7 responses indicate a majority, and < 7 responses indicate no agreement

Need for and design of another randomized trial of ECCO 2 R for patients with acute hypoxemic respiratory failure
During the post-meeting survey, 14/15 (93%, consensus) participants stated that a new randomized trial of ECCO 2 R is needed in patients with ARDS.A ΔP of ≥ 14-15 cmH 2 O was suggested by 12/14 participants (86%) as the primary inclusion criterion.No agreement existed for the primary endpoint, although mortality and the duration of MV were mentioned as suitable outcome parameters.Major bleeding (including central nervous system hemorrhage) was the most frequently indicated safety endpoint (8/12, 67%).

Table 2
Initiation and discontinuation thresholds for respiratory parameters when implementing ECCO 2 R in a sedated patient with mild-to-moderate ARDS a These criteria should be evaluated with sweep gas off on the ECCO 2 R device b Two participants declined to answer this question; level of agreement has been calculated using the total number of respondents c One participant declined to answer this question; level of agreement has been calculated using the total number of respondents A threshold of ≥ 80% of participants in agreement was defined as "consensus." A threshold of ≥ 50% of participants in agreement was defined as a "majority, " while < 50% was defined as "no agreement." ΔP driving pressure, ARDS acute respiratory distress syndrome, ECCO 2 R extracorporeal carbon dioxide removal, PaCO 2 partial pressure of carbon dioxide, P plat plateau pressure, RR respiratory rate

Table 3
Anticoagulation strategy when implementing ECCO 2 R in patients who are sedated and ventilated a All participants answered this question b All participants who used heparin (14/15) answered this question c Level of agreement for this question was calculated using the total number of respondents who use anti-Xa monitoring A threshold of ≥ 80% of participants in agreement was defined as "consensus." A threshold of ≥ 50% of participants in agreement was defined as a "majority, " while < 50% was defined as "no agreement"

3
Minimum requirements for ECCO 2 R therapy.A Minimum blood flow rate required for effective use of ECCO 2 R. All 15 participants answered this question.≥ 12 responses indicate consensus, ≥ 8 responses indicate a majority, and ≤ 7 responses indicate no agreement.B Minimum CO 2 removal rate for an ECCO 2 R device.14/15 participants answered this question.≥ 12 responses indicate consensus, ≥ 7 responses indicate a majority, and < 7 responses indicate no agreement

Table 4
Vascular access strategy when implementing ECCO 2 R